Benzo[h]cinnoline compound, a method of preparing said compound and a pharmaceutical composition

ABSTRACT

A benzo[h]cinnoline compound of the formula: ##STR1## wherein each of X and Y is hydrogen, halogen, trifluoromethyl, hydroxy, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, alkanoylamido having 2 to 4 carbon atoms, nitro, cyano, alkanoyl having 2 to 4 carbon atoms; Ar is phenyl or pyridyl which may be optionally substituted by at least one substituent selected from the group consisting of halogen, trifluoromethyl, hydroxy, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, amino, alkanoylamido having 2 to 4 carbon atoms, nitro and cyano; and the bond position indicated by dotted line is single bond or double bond, a method of preparing said compound and a pharmaceutical composition containing said compound. 
     Since these compounds possess high affinity for benzodiazepine receptor and antianxiety activity, they are useful as neutralizers to an excess dose of antianxiety agents or as antianxiety agents.

FIELD OF THE ART

The present invention relates to novel and pharmaceutically usefulbenzo[h]cinnoline compounds, methods of preparing said compounds andpharmaceutical compositions containing said compounds.

PRIOR ART

Journal of Medicinal Chemistry (J. Med. Chem.), Vol. 14, p. 262 (1971)discloses 2-substituted-benzo[h]cinnolin-3(2H)-ones. This literaturereports that all the compounds were found to be devoid of significantbiological activity, although all the compounds were evaluated foranalgesic, hypotensive, antiinflammatory, and CNS activities.

European Patent Application No. 124314 discloses3H-indeno-pyridazin-3-one derivatives with cardiotonic andantihypertensive activities.

DISCLOSURE OF THE INVENTION

The present inventors have made intensive studies in order to developuseful drugs. As a result of such investigations, the present inventorshave found that novel benzo[h]cinnoline compounds have potent affinityfor benzodiazepine receptor and antianxiety activity. The presentinvention, relates to benzo[h]cinnoline compounds represented by theformula: ##STR2##

In the formula, each of X and Y is hydrogen, halogen (e.g. fluorine,chlorine or bromine), trifluoromethyl, hydroxy, alkyl having 1 to 4carbon atoms (e.g. methyl, ethyl, propyl, isopropyl, butyl or isobutyl),alkoxy having 1 to 4 carbon atoms (e.g. methoxy, ethoxy, propoxy orbutoxy), amino, alkanoylamido having 2 to 4 carbon atoms (e.g.acetamido, propionamido or butyrylamido), nitro, cyano, alkanoyl having2 to 4 carbon atoms (e.g. acetyl, propionyl or butyryl); Ar is phenyl orpyridyl which may be optionally substituted by at least one substituentselected from the group consisting of halogen (e.g. fluorine, chlorineor bromine), trifluoromethyl, hydroxy, alkyl having 1 to 4 carbon atoms(e.g. methyl, ethyl, propyl, isopropyl, butyl or isobutyl), alkoxyhaving 1 to 4 carbon atoms (e.g. methoxy, ethoxy, propoxy or butoxy),amino, alkanoylamido having 2 to 4 carbon atoms (e.g. acetamido,propionamido or butyrylamido), nitro and cyano; and the bond positionindicated by dotted line is single bond or double bond.

The compounds of formula (I) of the present invention can be, forexample, prepared by the following Methods 1, 2 and 3.

(1) Method 1

The compound of the formula (I) can be prepared by reacting a compoundof the formula: ##STR3## wherein R is hydrogen or alkyl having 1 to 4carbon atoms (e.g. methyl, ethyl, propyl, isopropyl, butyl or isobutyl)and other symbols are as defined above, with a hydrazine compound of theformula:

    ArNHNH.sub.2                                               (III)

wherein Ar is as defined above, or acid addition salt thereof (e.g.hydrochloric acid salt), and then subjecting the thus obtained compoundof the formula: ##STR4## wherein each symbol is as defined above, to aring closure reaction.

The reaction of the compound of the formula (II) with the compound offormula (III) is carried out by refluxing under heating for 5 to 20hours in a suitable solvent, for example, in an alcoholic solvent suchas methanol, ethanol or propanol. In case the hydrazine compound offormula (III) is used as an acid addition salt, the above reaction iscarried out in the presence of an acid scavenger (e.g. sodium acetate,potassium acetate, sodium hydrogencarbonate, sodium carbonate orpotassium carbonate).

The ring closure reaction of the obtained compound of formula (IV) iscarried out by refluxing under heating for 5 to 10 hours in acetic acid.

(2) Method 2

The compound of the formula (I), wherein the bond position indicated bydotted line is double bond, can be synthesized by adding bromine inacetic acid dropwise to the compound wherein the bond position indicatedby dotted line is single bond [Journal of Medicinal Chemistry (J. Med.Chem.), Vol. 14, p. 262 (1971)], and preferably by adding 1 to 1.5 timesmoles of bromine dropwise to the compound of the formula: ##STR5##wherein each symbol is as defined above, at 20°-60° C. in acetic acid.

The compound of the formula (I) wherein the bond position indicated bythe dotted line is a double bond can also be prepared by reacting thecompound wherein the bond position indicated by a dotted line is asingle bond with sodium m-nitrobenzenesulfonate (Backmann Method,British Pat. No. 1,168,291.

(3) Method 3

The substituent X, Y or Ar of the compound obtained by the foregoingMethod 1 or 2 is converted into other substituent(s) according toconventional manners of organic chemical synthesis.

Such methods include, for example, reduction of a nitro group to anamino group; acylation of an amino group with a lower alkanoic acid; andconversion of an amino group into a cyano group (e.g. Sandmeyer reactionor Gattermann reaction).

When binding affinity for benzodiazepine receptor of the compounds offormula (I) thus obtained was measured by using a labeled-diazepam withtritium as a ligand, it has been found that said compounds possess highaffinities for benzodiazepine receptor of from 10⁻⁷ to 10⁻⁹ M, and sothey are useful as neutralizers to an excess dose of antianxiety agents.Furthermore, since some compounds exhibit an anti-pentylenetetrazoleactivity, they are also useful as antianxiety agents. The compounds ofthe present invention, when used as drugs, are advantageous because theydo not show sedative activity.

A displacement ability for benzodiazepine receptor is shown as follows:

Experimental method:

A specific binding for benzodiazepine receptor was determined accordingto the methods described in European Journal of Pharmacology, vol. 51,p. 129 (1978) and Life Science, vol. 20, p. 1201 (1977).

In brief, the crude synaptosomal membranes were prepared from thecerebral cortex of 9 to 10 week-old male Wistar rats and were suspendedin Tris-HCl buffer (pH 7.4). Various concentrations of test compoundsand tritiated diazepam (final concentration: 2 nM) were incubated at 4°C. for 20 minutes. Then the suspension was filtered through Whatman GF/Bglass fiber filters. Radioactivity of tritiated diazepam on the filterswas measured by liquid scintillation spectrometry. Specific binding wasdefined as the difference in the amount of radioactivity bound in theabsence and presence of 1.0×10⁻⁶ M unlabeled diazepam.

According to the above experimental method, the affinity of thecompounds of the present invention is evaluated as an ability todisplace tritiated diazepam from the binding site, and is represented asKi value. The results are summarized in the Table 1.

                  TABLE 1                                                         ______________________________________                                        Test Compound         Test Compound                                           (Example No.)                                                                            K i (M)    (Example No.)                                                                             K i (M)                                     ______________________________________                                         1         1.2 × 10.sup.-7                                                                    15          2.8 × 10.sup.-8                        2         1.9 × 10.sup.-7                                                                    16          1.4 × 10.sup.-8                        3         1.3 × 10.sup.-7                                                                    17          4.7 × 10.sup.-8                       11         1.6 × 10.sup.-8                                                                    18          9.0 × 10.sup.-8                       12         2.6 × 10.sup.-8                                                                    19          4.5 × 10.sup.-8                       13         6.6 × 10.sup.-9                                                                    20          3.4 × 10.sup.-8                       14         8.2 × 10.sup.-9                                                                    30          2.2 × 10.sup.-7                       ______________________________________                                    

Acute toxicity

The compound of Example 13 was orally or intraperitoneally administeredto mice. All mice survived at the oral dose of 1000 mg/kg and at theintraperitoneal dose of 250 mg/kg.

The compounds of the present invention, when used as drugs, can beadministered in the form of pharmaceutical composition such as tablets,capsules, granules, powder, syrup, injectable solutions, suppositoriesor the like by mixing a therapeutically effective amount of the compoundof the present invention with pharmaceutically acceptable additives(excipient, carrier, diluent and so on). The daily dose, for example, inan oral administration for human adults usually ranges from 5 mg to 500mg in a single or multiple doses.

Formulation Example

The tablets containing 20 mg of the compound (I) of the presentinvention can be prepared by the following composition.

    ______________________________________                                        Compound (I)            20.0   mg                                             Lactose                 68.5   mg                                             Corn starch             30.0   mg                                             Crystalline cellulose   20.0   mg                                             polyvinyl pyrrolidone K-30                                                                            2.0    mg                                             Talc                    4.0    mg                                             Magnesium stearate      0.5    mg                                                                     145.0  mg                                             ______________________________________                                    

Compound (I) is crushed with an atomizer to make a fine powder having anaverage particle size below 10 μ. The fine powder of Compound (I),lactose, corn starch and crystalline cellulose are mixed well in akneader and then kneaded with a binder prepared by polyvinylpyrrolidone. The wet mass is passed through a 200 mesh sieve and thendried in an oven at 50° C. The dry granule containing 3-4% of watercontent is forced through a 24 mesh sieve. Talc and magnesium stearateare mixed and compressed into tablets by using a rotatory tabletingmachine with a flat punch of 8 mm diameter.

The present invention will be explained by the following examples inmore detail, but these examples are not to be construed as limiting thepresent invention:

EXAMPLE 1

A mixture of 12 g of7-chloro-1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetic acid and 8.1 g ofphenylhydrazine in 150 ml of ethanol is refluxed under heating for 14hours. Then the ethanol is distilled off under reduced pressure, 100 mlof acetic acid is added to the residue and the mixture is refluxed underheating for 7 hours. After the acetic acid is distilled off, the residueis extracted with chloroform. The extract is washed with water, driedover magnesium sulfate anhydride and then the chloroform is distilledoff to give crystals. The precipitated crystals are collected byfiltration and recrystallized from alcohol to give 11.1 g of9-chloro-2-phenyl-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one ascolorless prisms, melting at 120°-122° C.

EXAMPLE 2

About half volume of 10 ml of solution of 3.9 g of bromine in aceticacid is added dropwise to a solution of 5 g of9-chloro-2-phenyl-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one in 150ml of acetic acid with stirring at room temperature. After the mixtureis heated up to 50° C. on a water bath, the remaining solution is addeddropwise. After stirring under heating at 50° C. for 2 hours, theprecipitated crystals are collected by filtration, washed with water andrecrystallized from ethanol to give 2.7 g of9-chloro-2-phenyl-5,6-dihydrobenzo[h]cinnolin-3(2H)-one as yellowleaflets, melting at 184°-186° C.

EXAMPLE 3

A mixture of 5 g of 1,2,3,4-tetrahydro-1-oxo-2-naphthylideneacetic acidand 3 g of phenylhydrazine in 100 ml of ethanol is refluxed for 10hours. The precipitated crystals are collected by filtration, washedwith ethanol and dissolved in 50 ml of acetic acid. The solution isrefluxed under heating for 8 hours and the acetic acid is distilled off.The residue is extracted with ethyl acetate and the extract is washedwith an aqueous sodium hydrogencarbonate solution. After drying overmagnesium sulfate anhydride, the solvent is distilled off and to theresidue is added ethanol. The precipitated crystals are collected byfiltration and recrystallized from ethanol to give 1.4 g of2-phenyl-5,6-dihydrobenzo[h]cinnolin-3(2H)-one as pale yellow needles,melting at 155°-157° C.

EXAMPLE 4

After a mixture of7-trifluoromethyl-1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetic acid andphenylhydrazine in ethanol is refluxed under heating for 10 hours, theethanol is distilled off. To the residue is added acetic acid and themixture is refluxed under heating for 7 hours. After the acetic acid isdistilled off, the residue is extracted with chloroform and the extractis washed with water and dried over magnesium sulfate anhydride. Thechloroform is distilled off to give2-phenyl-9-trifluoromethyl-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.

7-Trifluoromethyl-1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetic acid as astarting substance can be obtained as follows:

To an aqueous solution of sodium metaperiodate (NaIO₄) is added a smallamount of concentrated sulfuric acid with stirring. A solution oftartaric acid dissolved in water at 12°-24° C. is added dropwise to themixture with cooling at 12°-30° C. After the mixture is stirred at roomtemperature for 30 minutes, 7-trifluoromethyl-α-tetralone is added. Anaqueous solution of sodium hydroxide is added dropwise below 30° C., andthen ethanol is added. The reaction mixture is stirred at roomtemperature for 15 hours and further heated at 50°-60° C. for 4 hours.The resulting mixture is filtered and the filtrate is concentrated toabout half of volume. The concentrated filtrate is acidified withconcentrated hydrochloric acid on cooling to give7-trifluoromethyl-1,2,3,4-tetrahydro-1-oxo-2-naphthylideneacetic acid.

Furthermore, to a solution of the obtained7-trifluoromethyl-1,2,3,4-tetrahydro-1-oxo-2-naphthylideneacetic acid inacetic acid are added water and zinc powder. The mixture is stirredunder heating at 60° C. for 1 hour on a water bath and resultant mixtureis filtered. The filtrate is concentrated and the residue is acidifiedwith diluted hydrochloric acid to give7-trifluoro-methyl-1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetic acid.

EXAMPLE 5

To a mixture of9-chloro-2-(4-nitrophenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-onein ethanol and water is added iron powder with stirring at roomtemperature. To the mixture is added dropwise concentrated hydrochloricacid with stirring and heating up to 60° C. on a water bath. Theresulting mixture is further stirred under heating at the sametemperature and filtered, then the filtrate is concentrated. After theresidue is made alkaline by adding an aqueous solution of sodiumhydroxide, the mixture is extracted with chloroform. The extract iswashed with water and dried over magnesium sulfate anhydride. Thechloroform is distilled off to give2-(4-aminophenyl)-9-chloro-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.

EXAMPLE 6

A mixture of2-(4-aminophenyl)-9-chloro-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-onein acetic anhydride is refluxed under heating for 8 hours. After theacetic anhydride is distilled off, the residue is extracted withchloroform. The extract is washed with water and dried over magnesiumsulfate anhydride. The chloroform is distilled off to give2-(4-acetamidophenyl)-9-chloro-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.

EXAMPLE 7

2-(4-Aminophenyl)-9-chloro-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-oneis added to the mixture of water and concentrated hydrochloric acidwhich is cooled on an ice bath and then an aqueous solution of sodiumnitrite is added dropwise. The mixture is stirred under ice-cooling for30 minutes and then neutralized with sodium carbonate. The solution isadded dropwise with stirring to a solution of cuprous cyanide andpotassium cyanide which is previously prepared. The mixture is stirredunder ice-cooling for 30 minutes and allowed to stand overnight at roomtemperature. The precipitated crystals are collected by filtration togive9-chloro-2-(4-cyanophenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.

EXAMPLE 8

A solution of 7-nitro-1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetic acidand phenylhydrazine in ethanol is refluxed under heating for 10 hours.The ethanol is distilled off and to the residue is added acetic acid andthen the resulting mixture is refluxed under heating for 8 hours. Afterthe acetic acid is distilled off, the mixture is extracted withchloroform and the extract is washed with water. After drying overmagnesium sulfate anhydride, the chloroform is distilled off to give9-nitro-2-phenyl-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.

7-Nitro-1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetic acid as a startingsubstance can be prepared as follows:

To nitric acid (density=1.50) cooled with dry ice and methanol is added1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetic acid at -10 to -15° C. Theresulting mixture is stirred below 0° C. for 40 minutes and poured intoice. The precipitated crystals are collected by filtration to give7-nitro-1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetic acid.

EXAMPLE 9

To a mixture of9-nitro-2-phenyl-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one inethanol and water is added iron powder with stirring at roomtemperature. The mixture is heated up to 50° C. on a water bath withstirring and concentrated hydrochloric acid is added dropwise carefully.The resulting mixture is further stirred with heating at 80° C. and thefiltrate is concentrated. To the residue is added an aqueous sodiumhydroxide solution, and the alkaline solution is extracted withchloroform. The extract is washed with water, dried over magnesiumsulfate anhydride and the chloroform is distilled off to give9-amino-2-phenyl-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.

EXAMPLE 10

9-Amino-2-phenyl-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one obtainedby Example 9 is subjected to a similar reaction as Example 7 to give9-cyano-2-phenyl-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one, and theformer 9-amino compound is subjected to a similar reaction as Example 6to give9-acetamido-2-phenyl-4,4a,5,6-tetrahydrobenzo([h]cinnolin-3(2H)-one.

The following compounds can be prepared in a similar manner as the aboveexamples.

EXAMPLE 11

9-Methyl-2-(4-methylphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,melting at 177°-178° C.

EXAMPLE 12

2-(4-Chlorophenyl)-9-methyl-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,melting at 143°-145° C.

EXAMPLE 13

2-(4-Methoxyphenyl)-9-methyl-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,melting at 146°-149° C.

EXAMPLE 14

9-Methoxy-2-(4-methylphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,melting at 137°-139° C.

EXAMPLE 15

9-Chloro-2-(4-methylphenyl)-5,6-dihydrobenzo[h]cinnolin-3(2H)-one,melting at 184°-186° C.

EXAMPLE 16

9-Chloro-2-(4-methylphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,melting at 135°-138° C.

EXAMPLE 17

9-Chloro-2-(4-chlorophenyl)-5,6-dihydrobenzo[h]cinnolin-3(2H)-one,melting at 205°-207° C.

EXAMPLE 18

9-Chloro-2-(4-nitrophenyl)-5,6-dihydrobenzo[h]cinnolin-3(2H)-one,melting at 258°-259° C.

EXAMPLE 19

2-(4-Chlorophenyl)-9-fluoro-5,6-dihydrobenzo[h]cinnolin-3(2H)-one,melting at 176°-179° C.

EXAMPLE 20

2-(4-Chlorophenyl)-9-fluoro-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,melting at 158°-160° C.

EXAMPLE 21

2-(3-Trifluoromethylphenyl)-5,6-dihydrobenzo[h]cinnolin-3(2H)-one,melting at 120°-123° C.

EXAMPLE 22

2-(4-Chlorophenyl)-5,6-dihydrobenzo[h]cinnolin-3-(2H)-one, melting at156°-159° C.

EXAMPLE 23

8-Chloro-2-(4-chlorophenyl)-5,6-dihydrobenzo[h]cinnolin-3(2H)-one,melting at 201°-203° C.

EXAMPLE 24

8-Chloro-2-(4-chlorophenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,melting at 175°-177° C.

EXAMPLE 25

8-Chloro-2-phenyl-5,6-dihydrobenzo[h]cinnolin-3(2H)-one, melting at122°-124° C.

EXAMPLE 26

8-Chloro-2-phenyl-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one, meltingat 125°-127° C.

EXAMPLE 27

9-Chloro-2-(4-nitrophenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,melting at 177°-179° C.

EXAMPLE 28

9-Chloro-2-(4-fluorophenyl)-5,6-dihydrobenzo[h]cinnolin-3(2H)-one,melting at 174°-177° C.

EXAMPLE 29

9-Chloro-2-(4-fluorophenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,melting at 152°-153° C.

EXAMPLE 30

9-Fluoro-2-phenyl-5,6-dihydrobenzo[h]cinnolin-3(2H)-one, melting at180°-181° C.

EXAMPLE 31

9-Fluoro-2-phenyl-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one, meltingat 159°-160° C.

EXAMPLE 32

9-Chloro-2-(2-pyridyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,melting at 155°-157° C.

EXAMPLE 33

8-Chloro-2-(4-methylphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,melting at 120°-122° C.

EXAMPLE 34

8-Chloro-2-(4-methylphenyl)-5,6-dihydrobenzo[h]cinnolin-3(2H)-one,melting at 103°-107° C.

EXAMPLE 35

2-(4-Chlorophenyl)-9-methyl-5,6-dihydrobenzo[h]cinnolin-3(2H)-one,melting at 206°-207° C.

EXAMPLE 36

9-Methyl-2-phenyl-5,6-dihydrobenzo[h]cinnolin-3(2H)-one, melting at173°-175° C.

EXAMPLE 37

9-Methyl-2-phenyl-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one, meltingat 134°-135° C.

EXAMPLE 38

9-Methyl-2-(4-methylphenyl)-5,6-dihydrobenzo[h]cinnolin-3(2H)-one,melting at 190°-191° C.

EXAMPLE 39

2-(3-Methoxyphenyl)-9-methyl-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,melting at 160°-162° C.

EXAMPLE 40

2-(6-Chloro-2-pyridyl)-9-methyl-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,melting at 175°-177° C.

EXAMPLE 41

2-(4-Chlorophenyl)-9-methoxy-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,melting at 130°-132° C.

EXAMPLE 42

9-Methoxy-2-(4-methoxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one,melting at 107°-109° C.

EXAMPLE 43

8,9-Dichloro-2-(4-methoxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.

EXAMPLE 44

9-Fluoro-2-(4-methylphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.

EXAMPLE 45

2-(4-Fluorophenyl)-9-methoxy-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.

EXAMPLE 46

2-(4-Chlorophenyl)-8,9-dimethoxy-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.

EXAMPLE 47

8-Methoxy-2-(4-methylphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.

EXAMPLE 48

9-Hydroxy-2-(4-methylphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.

EXAMPLE 49

2-(4-Chlorophenyl)-8-hydroxy-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.

EXAMPLE 50

8,9-Dihydroxy-2-(4-methylphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.

EXAMPLE 51

9-Acetyl-2-(4-Chlorophenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.

EXAMPLE 52

9-Amino-2-(4-hydroxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.

Although the present invention has been adequately discussed in theforegoing specification and examples included therein, one readilyrecognizes that various changes and modifications may be made withoutdeparting from the spirit and scope of the present invention.

What is claimed is:
 1. A benzo[h]cinnoline compound of the formula##STR6## wherein X is hydrogen, halogen, trifluoromethyl, hydroxy,alkylhaving 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms,nitro, cyano or alkanoyl having 2 to 4 carbon atoms, and Y is hydrogen,halogen, hydroxy or alkoxy having 1 to 4 carbon atoms, with the provisosthat when Y is hydrogen, X is hydrogen, halogen, trifluoromethyl,hydroxy, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbonatoms, nitro, cyano or alkanoyl having 2 to 4 carbon atoms, when Y ishalogen, X is hydrogen or hydroxy, and when Y is alkoxy having 1 to 4carbon atoms, X is hydrogen or alkoxy having 1 to 4 carbon atoms, and Aris phenyl or 2-pyridyl which may be optionally substituted by asubstituent selected from the group consisting of halogen,trifluoromethyl, hydroxy, alkyl having 1 to 4 carbon atoms, amino,alkanoylamido having 2 to 4 carbon atoms, nitro and cyano; and the bondposition indicated by the dotted line is a single bond or double bond.2. The compound of claim1:2-(4-methoxyphenyl)-9-methyl-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.3. The compound of claim1:9-chloro-2-(4-methylphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.4. The compound of claim1:2-(4-chlorophenyl)-9-fluoro-5,6-dihydrobenzo[h]cinnolin-3(2H)-one. 5.The compound of claim1:2-(4-chlorophenyl)-9-fluoro-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.6. The compound of claim1:9-fluoro-2-phenyl-5,6-dihydrobenzo[h]cinnolin-3(2H)-one.
 7. Thecompound of claim1:2-(4-chlorophenyl)-9-methoxy-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.8. The compound of claim1:9-methoxy-2-(4-methoxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one9. A pharmaceutical composition for use as an antidote forbenzodiazepine-induced oversedation or for use as an antianxiety agentcomprising a therapeutically effective amount of a compound of claim 1and a pharmaceutically acceptable carrier therefor.